Patients with the syndrome of resistance to thyroid hormone (RTH) exhibit inappropriate section of TSH and elevated thyroid hormone levels due to mutations occurring in the beta gene of the thyroid hormone receptor (TR). The TR-beta gene encodes two isoforms and it is unclear whether both isoforms are equally important in negative regulation of TSH secretion by T/3 or how mutant TR-beta isoforms function to cause RTH. In vitro studies suggest that the TR-beta isoforms differ in their ability to mediate negative regulation of TRH and TSH subunit gene transcription by T/3 and vary in their function as dominant negative inhibitors of gene expression in RTH. Physiological studies in vivo are lacking, however, to confirm the significance of these findings. This proposal will test whether differences in TR-beta isoform regulation of TSH subunit gene expression by T/3 are relevant in vivo and are responsible for distinct syndromes of resistance to thyroid hormone (RTH). Three specific aims are proposed to elucidate the function of TR- beta isoforms in normal and T/3 resistance states. In the first aim, the specific role of the TR-beta2 isoform in the regulation of TRH and TSH subunit gene expression in vivo will be determined through targeted disruption of the TR-beta2 isoform in mice. In the second aim, the function of nuclear hormone receptor co-repressor protein (NCoR) on pituitary thyroid function will be determined in vivo by targeted over- expression of an NCoR inhibitor in transgenic mice. Finally, in third aim, the relative roles of the TR-beta isoforms in mediating distinct syndromes of resistance to thyroid hormone (RTH) will be assessed by expression of mutant TRs, in the context of either a TR-beta1 or TR- beta2 isoform, in the hypothalamus or pituitary or transgenic animals. The overall goal of this proposal is to clarify the function of TR-beta isoforms in vivo by utilizing physiologically relevant model systems. Determination of TR isoform-specific regulation of gene expression in vivo would yield novel insights into thyroid hormone action in man.